Liver fibrosis refers to a condition in which damaged liver tissue is modified into fiber tissue such as collagen without repair to normal liver cells as part of adaptive responses of the body, which are accompanied with toxic materials or various infectious, immune and metabolic diseases. In particular, it has been known that hepatic stellate cells (HSCs) transformed into myofibroblasts are proliferated and transferred to produce excessive connective tissue, leading to fibrosis of the liver. While the liver fibrosis is the adaptive response occurring in the body during repair of the damaged tissue, liver failure seems inevitable in that the liver is substituted by fiber tissue that cannot perform the unique functions of the liver such as metabolism in the body and bile secretion. When the liver fibrosis is consistently repeated, it develops into liver cirrhosis and leads to death. Therefore, development of a suitable therapeutic agent is the key task for the development of a new drug.
Currently, the development of a therapeutic agent for liver fibrosis has focused on whether a drug is able to inhibit the activity of HSCs, and as the conventional drug described above, penicillamine, 16,16-dimethyl prostaglandin E2, biphenyl dimethyl dicarboxylate, colchicine, glucocorticoid, malotilate, gamma interferon, pentoxifylline, pyridine-2,4-dicarboxylic-diethylamide or pyridine-2,4-dicarboxylic-di(2-methoxyethyl)amide are known (see Korean Patent No. 10-1086040). However, since these drugs have little effect or severe side effects, as of now, there is no effective therapeutic agent for liver fibrosis.
The human GPR119 gene is located on the X chromosome, and consists of a single exon. The human GPR119 gene has a different genetic composition from that of a mouse or rat, and there is a high similarity in expressed proteins between a human and a mouse. Like other receptors in the G protein-coupled receptor family, the human GPR119 has 7 transmembrane domains, but G proteins interacting therewith in cells have not yet been clearly identified.
It is known that GPR119 receptors are mainly present in pancreatic beta cells, and small intestinal enteroendocrine cells, for example, K cells and L cells. In the pancreas, GPR119 activation is known to increase cAMP levels using intracellular adenylate cyclase as a second messenger, and thus enhances insulin secretion by external glucose stimulation. Insulin stimulation is a glucose-dependent reaction, and thus the GPR119 receptor does not induce hypoglycemia, which is the disadvantage of the conventional therapeutic agent for diabetes. It has been reported that, in the small intestine, GPR119 activation stimulates secretion of GLP-1, GLP-2 and peptide YY from the L cells, and secretion of an insulinotropic peptide (GIP) from the K cells, and all of the GPR119 actions described above may predict the mechanism of anti-diabetes efficacy in response to a signal for stimulating a decrease in blood sugar level. It has been reported that, in practice, in an in vivo experiment using a mouse, administration of the GPR119 ligands effectively improves an insulin tolerance test (ITT) and a glucose tolerance test (GTT).
As endogenous GRP119 ligands, human lipid-like materials [N-acyl ethanolamines (NAEs) such as OEA, PEA and LEA] are used, and it has been reported that they have affinity to receptors such as PPAR alpha and TRPV1, as well as GPR119. Synthetic GPR119 ligands have been manufactured by large pharmaceutical companies including Arena Pharmaceuticals, GlaxoSmithKline (GSK), etc. Most of the synthetic GPR119 ligands are highly likely to be next generation therapeutic agents for diabetes, and particularly, MBX2982 and GSK1292263 are the most advanced materials entering phase II clinical trials.
According to conventional research, GPR119 expression in the liver was rarely found, and thus the efficacy of the GPR119 ligand on liver fibrosis had never been evaluated.